Neurofibrillary tangles in Niemann-Pick diseasetype CSeth Love,1 Leslie R. Bridges3 and C. Patrick Case2
* Department of Neuropathology, Frenchay Hospital, the2Departinent of Pathology, Southmead Hospital, Bristoland the ^Department of Neuropathology, University ofLeeds, Leeds, UK
Correspondence to: Dr S. Love, Department ofNeuropathology, Frenchay Hospital, Bristol BS16 1LE, UK
SummaryPost-mortem neuropathological examination of five cases ofNiemann-Pick disease type C revealed neurofibrillary tanglesin many parts of the brain. Tangles were a consistent findingin the hippocampus, hypothalamus, substantia innominata,midbrain pons and medulla. Other regions of the brain inwhich tangles were present included neocortex, basal ganglia,thalamus, cerebellar cortex in one case, and dentate nucleusin another. The tangles were argyrophilic, fluoresced underultraviolet light when stained with thioflavin S, and reactedstrongly with antibody to tau protein. Some of the tanglescould be immunostained for ubiquitin. Electron microscopy,performed in one of the cases, showed the tangles to consist
of paired helical filaments ultrastructurally identical to thoseof Alzheimer's disease. The distribution of the tangles in thecentral nervous system as a whole and also within manyindividual neurons corresponded fairly closely with that ofthe abnormal storage material. Both the tangles and thestorage material extended into, and distended, the proximalparts of many dendrites and axons. No A4/§ protein, eitherin the form of plaques or in the walls of blood vessels, wasdetected in any of the cases. Our findings suggest thatneurofibrillary tangles are a common feature of Niemann-Pick disease type C and that their formation may be areaction to the abnormal storage material.
Keywords: Niemann-Pick disease type C; neurofibrillary tangles; paired helical filaments; tau protein
IntroductionThe term Niemann-Pick disease includes several clinicallyand biochemically distinct disorders. These were subdividedby Crocker (1961) into types A, B, C and D on the basis ofthe tempo of the disease and the pattern of organ involvement.These different types of Niemann-Pick disease have beenfurther subclassified into group I, in which there issphingomyelinase deficiency, and group II, in which totalsphingomyelinase activity is normal. Group I includes typesA and B, and group II types C and D. Synonyms for TypeC Niemann-Pick disease include juvenile dystonic lipidosis,ophthalmoplegic lipidosis, neurovisceral storage disease withvertical supranuclear ophthalmoplegia and juvenile Niemann-Pick disease with sea-blue histiocytes. This disordercorresponds to Niemann-Pick disease type IIS in the schemeof Spence and Callahan (1989). The onset of Niemann-Pick disease type C may be in infancy, early childhood,adolescence or, occasionally, in adulthood (Fink et ai, 1989;Turpin et al., 1991). Clumsiness, ataxia, supranuclear gazeparesis, seizures and psychomotor retardation are thecommonest neurological manifestations (Fink et at., 1989;
Spence and Callahan, 1989; Turpin et al., 1991). Otherfeatures include myoclonus, narcolepsy and cataplexy. Turpinet al. (1991) noted that a psychosis may be the onlymanifestation of Niemann-Pick disease type C for severalyears. Hepatosplenomegaly is usually present and may bemarked or, particularly in older-onset cases, mild or evenabsent (Turpin et al., 1991; Hulette et al., 1992).
Neuropathological examination in cases of Niemann-Pickdisease type C reveals marked neuronal distension by weaklyor non-sudanophilic material that stains moderately well withperiodic acid-Schiff reagent (Lake, 1992). Other histologicalfeatures include the presence of swollen axons, particularlyin the brainstem and spinal cord, and foam cells in the bonemarrow, spleen and hepatic sinusoids.
Horoupian and Yang (1978), described a patient with typeC Niemann-Pick disease in whom Alzheimer-like neuro-fibrillary tangles were found at autopsy. The tangles weremost numerous in the frontal and temporal lobes, insula andbasal ganglia, and were shown by electron microscopy toconsist of paired helical filaments.
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Fig. 1 Section of frontal cortex from Case 1. Many of theneurons are distended by foamy cytoplasmic material. PTAH.Bar = 100 urn.
We present the neuropathological findings in five patientswith type C Niemann-Pick disease, from three separatefamilies. Our observations suggest that neurofibrillary tanglesare a common feature of this disorder. Their immuno-histochemical and ultrastructural appearances are identical tothose of neurofibrillary tangles in Alzheimer's disease. Thedistribution of the tangles in Niemann-Pick diseasecorresponds, by and large, with that of the accumulations ofstorage material in distended neurons, suggesting that theformation of neurofibrillary tangles may be a reaction to thestorage material.
diagnosis of type C Niemann-Pick disease. By 8 years, shehad developed spasticity of the limbs. When 10 years old,she began to have seizures. Over the next few years sheexperienced a progressive deterioration in motor power andintellect, difficulty with swallowing, and weight loss. Shedied at the age of 17 years.
Case 2B.H. was the only child of two healthy, unrelated parents.He was born by caesarean section after an obstructed labour,and had neonatal jaundice. He was noted to have mild tomoderate splenomegaly, the cause of which was notdetermined. His early development and schooling werenormal, although his mother later commented that she hadalways felt him to be rather poorly coordinated. He completedsecondary schooling (passing his GCSE examinations) butfound attendance of a college of further education emotionallystressful and had to leave. Psychological testing at that timerevealed him to have 'near normal overall intelligence withdeficits in certain spheres, such as left hemisphere tasks'. Hewas unsuccessful in obtaining work and complained thatpeople were 'after him' and 'reading his mind'. He becameincreasingly apathetic and forgetful. By the age of 20 yearshis clumsiness had worsened and he had developed astaggering gait and slurred speech. On review by neurologistsat 23 years, he had moderately severe generalized cerebellarataxia and occasional choreiform movements of the eyebrows.Tendon reflexes were brisk but plantar responses flexor.Power and sensation seemed to be reasonably well preserved.Routine haematological and biochemical investigations werenormal, as was a CT scan, and no firm clinical diagnosiswas made. His neurological deterioration continued over thefollowing 2 years and he experienced increasing difficultywith swallowing. At the age of 25 years, he was admitted tohospital with an empyema associated with a lobar pneumonia,from which he died.
Clinical summariesCase 1This girl, I.B., was the youngest of four siblings. She wasborn of healthy, unrelated parents. Her older brother hadbeen diagnosed on the basis of rectal and splenic biopsies ashaving type C Niemann-Pick disease. He died at the age of9 years. Two sisters were healthy but a female cousin, thethird child of a maternal aunt, also had Niemann-Pick disease.I.B. was a full-term baby but developed jaundice 3 days afterbirth and this persisted until day 8. During the first fewweeks of her life she suffered from frequent bruising, andbleeding from the umbilicus, mouth and rectum. At age 1year, a rectal biopsy revealed a neuronal storage disease. Sheattended a normal school until the age of 6 years, when herintellectual progress was noted to be slowing. At this timecerebellar incoordination and brisk tendon reflexes werenoted. Fibroblast culture from a skin biopsy supported the
Cases 3, 4 and 5P.T., G.T. and E.T. were brothers, born in 1954, 1961 and1964, respectively, of two healthy unrelated parents. A sister,born in 1957, has no neurological disease. The paternalgrandmother had suffered from Parkinson's disease in her60s but there was no other family history of note. All threebrothers had developed normally during early childhood.
P.T. performed poorly during his early schooling and wasdescribed as being 'somewhat hyperactive'. At 11 years, hewas admitted to a special residential school. He was laterplaced in a normal secondary school but was unable to copewith the work. At 17 years, he was admitted to a psychiatrichospital with a 'thought disorder' characterized by excessive,meaningless conversation, and was given a diagnosis ofschizophrenia. He was also noted to show abnormal fidgetymovements. Over the next 5 years he spoke less and lessand the fidgety movements became less prominent. On
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Table 1 Distribution of histological abnormalities within the central nervous system
*n,t,d = occasional distended neurons (dn), neurofibrillary tangles (t), swollen neurites (sn); N,T,D =numerous distended neurons (DN), neurofibrillary tangles (T), swollen neurites (SN); g,G = moderate(g) or marked (G) neuronal loss and gliosis; 0 = no abnormalities; — = not available for examination.
examination at the age of 22 years, he was mute, withdystonic movements of all four limbs, which also showed amarked increase in tone and brisk reflexes. His toes wereheld in fixed extension so that plantar responses could notbe assessed. At about this time investigations into theneurological illness of his younger brother, G.T. {see below),pointed towards a diagnosis of Niemann-Pick disease and itwas thought likely that the same disorder was responsiblefor P.T.'s neurological findings. He died of bronchopneumoniaat the age of 33 years.
G.T. attended normal lower and secondary schools, where
he was described as 'slow'. After leaving school, he wasunable to hold a job. When 18 years of age, he complainedof hearing voices and, after he had been found to showposturing and waxy flexibility, was admitted to a psychiatrichospital. He failed to respond to medication but was reportedto show some improvement after electroconvulsive therapy.However, over the following 2 years he became increasinglyconfused and 'restless'. On examination at 20 years of age,he was found to be severely demented, with chorea. His eyemovements could not be assessed. Examination of a bonemarrow aspirate and a biopsy showed large numbers of
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Fig. 2 Sections of hippocampus from Case 2. A, large numbers of neurofibrillary tangles are present, particularly in the CA1 field(arrows). Modified Bielschowsky silver impregnation. Bar = 500 urn. B, at higher magnification the skeins of argyrophilic materialwithin the neurofibrillary tangles are clearly visible. Bar = 20 urn. C, in a section stained with thioflavin S, the neurofibrillary tanglesfluoresce strongly under ultraviolet light. Bar = 100 um
foamy macrophages and occasional large cells with theappearance of sea-blue histiocytes. A diagnosis was madeof 'probable sea-blue histiocyte variant of Niemann-Pickdisease'. Death from bronchopneumonia occurred at the ageof 23 years.
E.T. also attended normal lower and secondary schoolsand subsequently studied catering at college, where he passedthe first part of a City and Guilds catering examination. Itwas shortly after this, at the age of 18. that he was first seenby a neurologist, in the course of investigation of the disorderaffecting P.T. and G.T. He showed evidence of perseveration,echolalia and constructional and ideomotor apraxia. He hadpoor recollection of current events and could not performmental arithmetic. He was clumsy at sequential motor tasksbut did not show chorea. Examination of eye movementsdisclosed an inability to look downwards. Over the courseof the next few years he became increasingly demented and
manifested choreiform movements. Death from broncho-pneumonia occurred at the age of 25 years.
Methods and resultsGeneral autopsy findingsGross abnormalities present in all cases, in addition tobronchopneumonia, were a mild to moderate degree ofhepatosplenomegaly and generalized enlargement of lymphnodes to a diameter of ~2 cm. The lymph nodes had a smoothsurface and appeared pale pink on sectioning.
In all cases, histological examination revealed many large,foamy macrophages within the lymph node sinuses andspleen. Kupffer cells in the liver were similarly distended byfoamy cytoplasmic material that reacted with periodic acid-Schiff reagent in cryostat sections, but the hepatocytes
appeared normal. Scattered foamy macrophages were presentin the bone marrow and in the alveolar spaces and interstitiumof the lung, even in areas not obviously affected bybronchopneumonia.
Neuropathological findingsThe brains from Cases 1,2,3 and 5 were fixed intact beforesectioning. That from Case 4 was sliced fresh and only limitedmaterial was available for neuropathological examination. Inonly two cases (2 and 5) was the spinal cord examined.
The brains varied in macroscopic appearance. That of Case1 weighed 735 g. Although small, the cerebral hemispheresdid not appear atrophic but the cerebellum was obviouslyshrivelled and abnormally firm. The brains of Cases 2 and 4weighed 1320 g and 1250 g, respectively, and appearedmacroscopically unremarkable. In Case 3 the brain weighed1190 g and showed generalized cerebral atrophy that involvedthe cortex and deep grey matter and was associated withmoderate lateral and third ventricular dilatation. Thecerebellum and brainstem appeared small but without anydiscernible focal abnormalities. The brain of Case 5 weighed1224 g; sectioning revealed some dilatation of the lateral andthird ventricles and thinning of the corpus callosum. Thecerebellum appeared mildly atrophic.
In all cases, histological examination showed markedcytoplasmic distension of many neurons in the neocortex byfoamy material, with displacement of the nucleus towardsthe edge of the cell (Fig. 1). In cryostat sections the distendedneurons could be stained with periodic acid-Schiff reagentand, faintly, with Sudan black and oil red O, but processingof the tissue for embedding in paraffin wax resulted inloss of staining of the abnormal cytoplasmic material. Thenumbers of swollen neurons in the entorhinal cortex,subiculum and cornu ammonis varied from case to case(Table 1).
A striking feature in all cases was the presence of manyneurofibrillary tangles, particularly in the CA1 and CA2fields of the cornu ammonis (Fig. 2) but also, in variablenumbers, throughout the cerebral cortex (Table 1). In theneocortex the tangles predominantly involved neurons inlaminae 3, 5 and 6. Many of the tangle-bearing neuronsshowed, in addition, obvious cytoplasmic distension by foamymaterial (Fig. 3). In Cases 2, 3 and, to a lesser extent, Case1, the cytoplasmic distension also involved some of thedendrites and proximal axonal segments. Some of theresulting axonal and dendritic swellings also containedneurofibrillary tangles, usually in continuity with tangles inthe neuronal soma (see Immunohistochemistry, below). Thetangles were intensely argyrophilic and fluoresced underultraviolet light in thioflavin S preparations (Fig. 2C).Thiofiavin S also stained scattered neurites that were notobviously distended. No diffuse or compact neuritic plaqueswere present in any of the cases, nor was there any amyloidangiopathy.
Many distended neurons were noted in the basal ganglia,
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2i
Fig. 3 CA1 field of hippocampus (Case 3). Two of the neuronsdistended by foamy material also contain neurofibrillary tangles(arrows). Haematoxylin and eosin. Bar = 20 urn.
thalamus, hypothalamus and substantia innominata of thoseof the cases with material available for examination (Table I).The appearance and staining characteristics of the cytoplasmicmaterial were identical to those of the distended neurons inthe cerebral cortex. Scattered neurons contained typicalneurofibrillary tangles and, as in the cerebral cortex, therewere also moderate numbers of neurites of normal calibrethat were strongly fluorescent in thioflavin S preparations.Included in the pallidum of Case 2 were occasional clustersof swollen, argyrophilic neurites.
Examination of all cases, except Case 4 (from whichappropriate blocks were not available), revealed markedfoamy swelling of neurons in the midbrain. This was mostpronounced in the extraocular motor nuclei and the substantianigra. Also present were many neurofibrillary tangles andswollen neurites, the latter particularly in the pars compactaof the substantia nigra.
The appearance of the cerebellum varied considerablyfrom case to case. In Case 1 there was severe loss of Purkinjeand granule cells, with proliferation of Bergmann astrocytesand isomorphic gliosis. Amongst the remaining neurons inthe cerebellar cortex were some that were distended by foamycytoplasmic material. Some of these were in the Purkinjecell layer. Others had relatively large nuclei, resembling those
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Fig. 4 Sections of cerebellar vermis from Case 1. A, there is obvious loss of Purkinje and granule cells, and proliferation of Bergmannastrocytes. A few, scattered neurons with relatively large nuclei and foamy cytoplasm (arrows) are present in the granule cell layer.Haematoxylin and eosin. Bar = 100 (xm. B, higher magnification view of the granule cell layer which includes two swollen neurons(arrows). The one towards the bottom right of the figure contains a neurofibrillary tangle. Palmgren silver impregnation. Bar = 20 urn.
of Purkinje cells, but were scattered amongst the granulecells (Fig. 4A) and, in some cases, contained neurofibrillarytangles (Fig. 4B). In Case 2, occasional neurons in the dentatenucleus were distended and some contained neurofibrillarytangles. The cortex was well preserved. There was someaccumulation of foamy cytoplasmic material in scatteredPurkinje cells in Cases 3-5, associated with moderate lossof Purkinje cells and cortical gliosis in Cases 3 and 5.
Distended neurons were present in the tegmentum of thepons (including the locus ceruleus) and medulla, and in theinferior olivary nuclei, which also showed striking, irregularlybeaded, axonal and dendritic enlargement in Cases 1 and 2(Fig. 5). Neurofibrillary tangles and swollen neurites werepresent in the hindbrain in varying numbers (Table 1).
In the two cases in which the spinal cord was examined(Cases 2 and 5) the grey matter contained scattered distendedneurons. No histological abnormalities were noted in thepituitary and dorsal root ganglia in Case 2, the only case inwhich these were available for examination.
and A4/p protein (Dako), and rabbit polyclonal anti-ubiquitin(Dako), by a conventional avidin-biotin-horseradish peroxi-dase method. Controls included sections from cases ofAlzheimer's disease and from normal brains, as well assections immunostained with irrelevant antibodies or fromwhich the primary antibody was omitted.
Antibody to tau protein immunostained not only theneurofibrillary tangles but also many of the swollen axonsand dendrites (Figs 6-8). Scattered neurites of normal calibrewere also immunostained for tau; these were particularlynumerous in the CA1 field of the cornu ammonis and inareas of high tangle density in the neocortex, amygdala anddeep grey nuclei, particularly the hypothalamus. Some of thedistended neurons and neurites showed dispersed, granularimmunoreactivity rather than clear delineation of well formedtangles (Fig. 6). Many but not all of the tangles reacted withanti-ubiquitin. No A4/p protein immunoreactivity was notedin any of the cases, even after the sections had been digestedfor up to 30 min in 99% formic acid.
ImmunohistochemistryMultiple sections of brain from all cases were immunostainedwith mouse monoclonal antibodies to tau protein (Sigma)
Electron microscopyExamination of sections of temporal neocortex from Case 2revealed many neurons to be distended by polymorphous
Tangles in Niemann-Pick disease 125
Fig. 5 Section of inferior olivary nucleus (Case 2), showingirregular beading and distension of neurites. ModifiedBielschowsky silver impregnation. Bar = 100 nm.
cytoplasmic bodies typical of Niemann-Pick disease groupII (including type C Niemann-Pick disease). Also presentwere neurofibrillary tangles, composed of closely packedpaired helical filaments, morphologically identical to thosefound in Alzheimer's disease. In many of the affectedneurons, skeins of paired helical filaments were separated bythe polymorphous cytoplasmic bodies (Fig. 9).
DiscussionNeurofibrillary tangles are a feature of several disorders,including Alzheimer's disease (Kidd, 1964; Wisniewski et al.,1976), progressive supranuclear palsy (Steele et al., 1964;Tellez-Nagel and Wisniewski, 1973), post-encephaliticparkinsonism (Hallervorden, 1933, 1935), Guam parkin-sonism-dementia complex (Hirano et al., 1961), subacutesclerosing panencephalitis (Malamud et al., 1950; Mandyburet al., 1977), myotonic dystrophy (Kiuchi et al., 1991) anddementia pugilistica (Corsellis et al., 1973). However, to ourknowledge, apart from Niemann-Pick disease type C, theonly neuronal storage disorder in which neurofibrillary tangleshave been described is Kufs' disease. Kornfeld (1972)described, but did not illustrate, neurofibrillary tangles in thehippocampus of a patient with Kufs' disease. In an earlier
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Fig. 6 Temporal neocortex, occipitotemporal gyrus (Case 1).The section includes several swollen neurons, some withgranular cytoplasmic tau immunoreactivity. There is continuitybetween one of the swollen neurons and an axonal swelling(arrow), also labelled with anti-tau. Anti-tau with haematoxylincounterstain. Bar = 20 urn
case report, Chou and Thompson (1970) noted numerousneurofibrillary tangles in the hypothalamus and midbrain ofa patient also diagnosed as having Kufs' disease although,as noted by Horoupian and Yang (1978), the electronmicrographs illustrate neuronal cytosomes with closeresemblance to those of Niemann-Pick disease type C. Thenosology of the case of 'juvenile amaurotic idiocy' withneurofibrillary tangles, reported by Loken and Cyvin (1954)is unclear; although neurons were described as containingsudanophilic material, none was ballooned, and argyrophilicplaques were noted in the cerebral cortex.
Several animal models of Niemann-Pick disease type Chave been described, including two in different strains ofmouse (Pentchev et al., 1984; Miyawaki et al., 1986) and afeline sphingolipidosis (Lowenthal et al., 1990). These sharemost of the biochemical, histological and ultrastructuralfeatures of the human disorder and have contributedsubstantially to our identification of the genetic defect in
126 5. Love et al.
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Fig. 7 Inferior temporal gyrus (Case 2). The section includesseveral tau-immunoreactive neurofibrillary tangles in neuronalsomata. Occasional tangles extend into the proximal axonalsegment (arrows) or apical dendrite (arrowhead). Anti-tau withhaematoxylin counterstain. Bar = 100 u.m.
Fig. 8 Section through the oculomotor nucleus (Case 5), whichincludes several swollen neurons, one also containing aneurofibrillary tangle (arrow). Anti-tau with haematoxylincounterstain. Bar = 20 um.
Niemann-Pick disease in man (see below). As far as we areaware, neurofibrillary tangles have not been described in anyof the animal models of type C Niemann-Pick disease.However, recent observations of the cerebellar pathology of
the murine models are of interest in relation to our ownfindings in Case 1, especially the presence of large distendedneurons in the granule cell layer. Degeneration of Purkinjecells is well recognized to occur in some patients withNiemann-Pick disease type C (Anzil et al., 1973; Gilbertet al., 1981) and is a constant finding in both murine modelsof this disorder (Tanaka et al., 1988; Higashi et al., 1993).Tanaka et al. (1991) studied the immunohistochemicalexpression of P400 protein, a membrane glycoprotein inPurkinje cells, in the C57BLK/KsJ spm/spm mouse. Theyfound evidence not only of neuronal degeneration but alsoof a Purkinje cell migration defect. Heterotopic Purkinje cellswere present in the cerebellar white matter and, in smallnumbers, in the deep cerebellar and lateral vestibular nuclei.It is, similarly, possible that some of the distended neuronsin the granule cell layer in Case 1 were heterotopicPurkinje cells.
Although conventional biochemical assays of affectedtissues show normal total sphingomyelinase activity inNiemann-Pick disease type C, the activity of certainisoelectric forms may be reduced (Gilbert et al., 1981).Sphingomyelinase activity is usually reduced in culturedfibroblasts. The principal metabolic abnormality in thisdisorder is thought to be an accumulation of unesterifiedcholesterol within lysosomes and Golgi apparatus, due to anabnormality affecting intracellular transport of cholesterol ora primary defect of cholesterol esterification (Blanchette-Mackie et al., 1988; Vanier et al., 1988). The reduction inlysosomal sphingomyelinase activity seems to be a secondaryeffect of the intracellular accumulation of cholesterol (Thomaset al., 1989). Kurimasa et al. (1993) showed that transfer ofthe human chromosome 18 to 3T3 cell lines derived fromhomozygous sphingomyelinosis mice (C57BLK/KsJ spm/spm), which have murine Niemann-Pick disease type C,restored cholesterol metabolism to normal. Subsequent lossof 18pter—pi 1.3 and 18q21.3-qter during subcloning of thecell lines caused reaccumulation of cholesterol, suggestingthat the gene could be mapped to one of these two segments.More recently, linkage analysis by Carstea et al. (1993)indicated that the NPC gene is located in the pericentromericregion of chromosome 18, probably on the short arm of thechromosome.
Studies by Vanier and colleagues have identified bio-chemical heterogeneity in relation to the uptake of low densitylipoprotein and accumulation of cholesterol in Niemann-Pickdisease type C (Vanier et al., 1988, 1991). Vanier et al.(1991) defined three biochemical groups: a 'classical' group,accounting for 86% of patients, and 'variant' and 'inter-mediate' groups, each accounting for 7%. Prenatal diagnosisof the disease is now possible, at least in families with'classical' Niemann-Pick disease type C, by study of theprocessing of cholesterol in cultured villus or amniotic fluidcells (Vanier et al., 1992).
The pathogenesis of the neurofibrillary tangles in Niemann-Pick disease type C is not clear but the diversity of acquiredand inherited diseases in which neurofibrillary tangles occur,
Tangles in Niemann-Pick disease 127
Fig. 9 Electron micrograph showing part of the cytoplasm of a neuron in the temporal cortex (Case 2). Bundles of filaments with apaired helical structure are separated by pleomorphic cytosomes typical of Niemann-Pick disease group II. Bar = 200 nm.
128 S. Love et al.
suggest that these may represent a final common pathway ofa range of cellular insults. One interpretation of the reasonablyclose correspondence between the distribution of distendedneurons and that of the tangles is that the accumulatedcytoplasmic material induces tangle formation, presumablyby directly or indirectly affecting the metabolism of tauprotein. Of possible relevance are the observations on theintracellular distribution of the abnormal cytoplasmic materialand the neurofibrillary tangles: close intermingling of thestored material with tau immunoreactivity or, in the electronmicroscope preparations, with paired helical filaments, wasnoted not only in neuronal somata but also in the swollendendrites and axons.
The development of neurofibrillary tangles in Niemann-Pick disease type C may be a manifestation of morewidespread cytoskeletal abnormalities. The presence of 'dys-trophic' axonal swellings in Niemann-Pick disease type Chas long been recognized. Electron microscopy of theswellings has revealed accumulations of filaments, degener-ating organelles and amorphous material (Elleder et al.,1985). Similar observations have been made in animalmodels of Niemann-Pick disease (see above). Cytoskeletalabnormalities may also play a role in the pathogenesis of thecholestatic liver disease that affects over half of neonates orinfants with Niemann-Pick disease type C (Kelly et al.,1993) and was noted in Cases 1 and 2 in the present series.Ultrastructural examination of the liver of an affected 20week foetus (Dumontel et al., 1993) revealed hyperplasia ofpericanalicular microfilaments, a feature of early cholestasis;the authors suggested that the cholestasis of this disordermay be due to toxic metabolite-induced dysfunction of hepaticmicrofilaments.
AcknowledgementsWe wish to thank Dr M. J. Campbell for permission to reportthe clinical findings in two of the cases.
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